Several anti-tumor drugs, including taxol, cisplatin and vincristine, when administered, have adverse side-effects on individuals, including toxic sensory or sensorimotor neuropathy and neuronal dysfunction. For example, taxol is a plant alkaloid that promotes the assembly of microtubules and stabilizes them. Clinical trials have demonstrated taxol's antineoplastic activity against solid tumors, including metastatic melanoma. However, taxol, cisplatin and vincristine cause toxic sensory neuropathy, and are cytotoxic to dorsal root ganglion neurons. Additionally, certain anti-viral drugs, including dideoxycytidine and dideoxyinosine, when administered, cause toxic neuropathy.
Co-treatment of individuals with the above-discussed anti-tumor and antiviral drugs, along with growth factors, including nerve growth factor, has previously been shown to prevent neuronal death in in vitro experiments (see Peterson and Crain, Science, Vol. 217, p. 337 (1982)). In addition, it has been demonstrated that administration of nerve growth factor to rat and mouse models of taxol (see Apfel et al., Ann. Neurol., Vol. 29, pp. 87-90 (1991)) and diabetic neuropathy (see Apfel et al., Brain Res., In Press (1993)) prevents neuropathy. However, nerve growth factor and other growth factors have been shown to cause hyperalgesic side-effects.
Nerve growth factor (NGF) has been shown to elicit rapid biochemical and structural changes in nerve cells (see Greene et al., Ann. Rev. Neurosci., Vol. 3, pp. 353-402 (1980) and Levi et al., Ann. Rev. Pharmacol., Vol. 31, pp. 205-228 (1991)). For example, the application of NGF to PC12 cells results in increased cystolic Ca.sup.2+ concentration within minutes, due to enhanced Ca.sup.2+ influx as well as release from internal stores (see Lazarovici et al., J. Neurosci. Res., Vol. 23, pp. 1-8 (1989)).
Furthermore, nerve growth factor has been shown to increase the Ca.sup.2+ -dependent release of dopamine and norepinephrine from PC12 cells within a few minutes (see Nikodijevic et al., J. Neurosci. Res., Vol. 26, pp. 288-295 (1990)), and the release of histamine from mast cells within minutes in vitro in the presence of lysophosphatidyl serine (see Bruni et al., FEBS Lett., Vol. 138, pp. 190-192 (1982); Sujiyama et al., Arch. Oral Biol., Vol. 30, pp. 93-95 (1985); and Mazurek et al., FEBS Lett., Vol. 198, pp. 315-320 (1986)). Nerve growth factor has also been found to enhance endogenously released adenosine effects on PC12 cells (see Rice et al., J. Neurochem., Vol. 44, pp. 1588-1592 (1985)), and may account for previous reports that nerve growth factor rapidly stimulates cyclic AMP levels in PC12 and other types of neurons (see Nikodijevic et al., Proc. Nat'l. Acad. Sci. USA, Vol. 72, pp. 4769-4771 (1975); Schubert et al., Nature, Vol. 273, pp. 718-723 (1978); and Skaper et al., J. Neurochem., Vol. 32, pp. 1845-1851 (1979)). Finally, it has been reported that nerve growth factor administration causes hyperalgesic response in rodents (see Levi-Montalcini et al., Prog. in NeuroEndocrineImmunol., Vol. 3, pp. 1-10 (1990) and Lewin et al., J. Neurosci., Vol. 13, pp. 2136-2148 (1993)).
Because nerve growth factor and other growth factors are of great use in limiting toxic sensory neuropathy and neuronal dysfunction, a great need exists to prevent hyperalgesia and other undesirable side-effects caused by the administration of nerve growth factor and other growth factors.
It is therefore an object of this invention to provide a method of preventing hyperalgesia and other undesirable side-effects caused by the administration of nerve growth factor and other growth factors.
It is a further object of this invention to provide a composition capable of simultaneously preventing toxic sensory neuropathy and neuronal dysfunction and preventing growth factor-associated hyperalgesia.